Second Interim Analysis Shows OS Improvement with Adjuvant Olaparib for Germline BRCA1/2-associated, HER2-negative Early Breast Cancer

With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in overall survival (OS) with adjuvant olaparib compared with placebo for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 and high-risk, HER2-negative early breast cancer. Adjuvant olaparib maintained improvements in the previously reported, statistically significant endpoints of invasive-disease-free survival (IDFS) and distant-disease-free survival (DDFS). With 3.5 years of median follow-up there were 2 acute myeloid leukaemia (AML)/ myelodysplastic syndrome (MDS) cases (0.2%) with olaparib and 3 (0.3%) with placebo. With 1-year of additional follow-up, no new safety signals were identified with adjuvant olaparib compared to placebo. The findings are published by Prof. Andrew Tutt of The Institute of Cancer Research, Guy’s Hospital Cancer Centre, King’s College London and colleagues on 10 October 2022 in the Annals of Oncology.

The authors wrote in the study background that breast cancers associated with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 are characterised by high-grade disease with most tumours associated with pathogenic or likely pathogenic variants in germline BRCA1 being triple-negative, whereas most associated with pathogenic or likely pathogenic variants in germline BRCA2 are hormone receptor-positive and HER2-negative, and often associated with high-risk classification on RNA-based prognostic assays.

Patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 associated early breast cancer and high-risk clinico-pathological features remain at increased risk for recurrence following standard multimodality therapies. The OlympiA study was designed to determine whether 1 year of adjuvant olaparib could improve outcomes in this population. This phase III, double-blinded, placebo-controlled study randomly assigned 1,836 eligible patients from 2014 to 2019 to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers.

Following review of the first pre-specified interim analysis of the primary endpoint of IDFS, the independent data monitoring committee recommended full analysis. With a median follow-up of 2.5 years, patients randomised to olaparib had statistically significant and clinically meaningful improvement in IDFS compared to placebo (hazard ratio [HR] 0.58, 99.5% confidence interval [CI] 0.41 to 0.82; p < 0.001) and DDFS (HR 0.57, 99.5% CI 0.39 to 0.83; p < 0.001), which corresponded to absolute improvements at 3 years in IDFS of 8.8% and in DDFS of 7.1%. The number of deaths in the olaparib group were fewer than in the placebo group (59 vs 86), but the difference (HR 0.68, 99% CI 0.44 to 1.05; p = 0.02) did not meet the pre-specified boundary for statistical significance for OS (p < 0.01). The safety analysis was consistent with the experience in metastatic breast cancer setting and provided no early evidence of increased risk of AML/MDS.

The second interim analysis of OS was pre-specified to occur when 330 IDFS events had been reported in the study population and in the latest article published in the Annals of Oncology, the study investigators reported the results of this OS analysis with updates of IDFS, DDFS, and safety information. Statistical significance for OS at this interim analysis required p < 0.015.

With median follow-up of 3.5 years, the second interim analysis of OS demonstrated significant improvement in the olaparib group relative to the placebo group (HR 0.68; 98.5% CI 0.47 to 0.97; p = 0.009). Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively.

Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of AML/MDS. The authors commented that although the key long-term safety endpoint of AML/MDS will require longer follow-up for complete assessment, the low incidence with a median follow-up of 3.5 years coupled with the absence of new cases since the initial report is reassuring.

The authors concluded that pre-specified second interim analysis of OlympiA with a median follow-up of 3.5 years demonstrates a statistically significant improvement in OS with olaparib compared to placebo and maintenance of clinically meaningful absolute improvements in the previously reported statistically significant primary endpoint of IDFS and the secondary endpoint of DDFS. Subgroup analyses for all 3 endpoints demonstrate benefit irrespective of hormone receptor status, neoadjuvant versus adjuvant chemotherapy, prior use of platinum for breast cancer and type of pathogenic variant in germline BRCA. The safety and tolerability profile of olaparib in this study remain consistent with that observed in previous studies. The results highlight the importance of testing for pathogenic or likely pathogenic variants in germline BRCA1/2 in patients with newly diagnosed high-risk early breast cancer.

Reference

Geyer Jr. CE, Garber JE, Gelber RD, et al., on behalf of the OlympiA Clinical Trial Steering Committee and Investigators. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high risk, early breast cancer. Annals of Oncology; Published online 10 October 2022. DOI: https://doi.org/10.1016/j.annonc.2022.09.159

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